Hemochromatosis is an autosomal disorder of iron metabolism wherein the body accumulates excess iron. The hemochromatosis (HH) gene was originally shown to be linked to the MHC on chromosome 6p21 (Simon et al. Gut 17:332-334 (1976)). The HH gene was recently cloned by Feder et al. (Nature Genetics 13:399-408 (1996)).
Fine structure mapping of the region to which the HH gene was mapped makes possible the identification of candidate sequences comprising the HH genes, along with structural elements for regulation and expression and neighboring genes.
A variety of techniques is available for fine structure mapping, including direct cDNA selection, exon-trapping, and genomic sample sequencing. The direct selection approach (Lovett et al. Proc. Natl. Acad. Sci. U.S.A. 88:9628-9623 (1991)) involves the hybridization of cDNA fragments to genomic DNA. This technique is extremely sensitive and capable of isolating portions of rare transcripts. Exon-trapping (Church et al. Nature Genetics 6:98-105 (1994)) recovers spliced introns from in vivo expressed genomic DNA clones and produces candidate exons without requiring any prior knowledge of the target's gene expression. High-through-put genomic DNA sequencing with comparison of the sequence data to databases of expressed sequences has also been used, such as in the positional cloning of the Werner syndrome gene (Yu et al. Science 277:258-262 (1996)) and in cloning by homology of the second Alzheimer's disease gene on chromosome 1 (Levy-Lahad et al. Science 269:973-977 (1995)).
Thus, a need exists for both methods for fine structure mapping and a fine structure map of the region of the chromosome to which the HH locus maps. This and other needs are addressed by the present invention.